Synthesis of 1-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-2-morpholinoethane-1,2-dione analogues and their inhibitory activities with reduced cytotoxicity in lipopolysaccharide-induced BV2 cells

Bioorg Med Chem Lett. 2023 Jan 1:79:129061. doi: 10.1016/j.bmcl.2022.129061.

Sung-Hwa Yoon ¹, Duk-Yeon Cho ², Jun-Hyuk Han ², Dong-Kug Choi ², Eunha Kim ¹, Ju-Young Park ³

Affiliations

1 Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea.
2 Department of Biotechnology, Konkuk University, Chungju 27478, Republic of Korea.
3 Molecular Science and Technology Research Center, Ajou University, Suwon 16499, Republic of Korea. Electronic address: pink1209@ajou.ac.kr.

PMID: 36371018 DOI: 10.1016/j.bmcl.2022.129061

Abstract

A series of rimonabant analogues, where the N-aminopiperidine moiety was replaced by various amines and an additional carbonyl group, were synthesized and their inhibition of nitric oxide (NO) production was evaluated in lipopolysaccharide (LPS)-induced BV2 microglial cells. Among the synthesized compounds, the morpholine analogue 7y (IC₅₀ = 4.71 ± 0.11 μM) showed significantly higher inhibitory activity than rimonabant (IC₅₀ = 16.17 ± 0.56 μM), and suppressed NO production dose-dependently without cytotoxicity. In addition, 7y inhibited the expression of iNOS, COX-2 and pro-inflammatory cytokines and attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB) and ERK MAPK phosphorylation in BV2 cells. These results demonstrated that 7y exerted anti-inflammatory effects by ERK pathway in BV2 cells, which can be used for the prevention and treatment of neuroinflammatory diseases.

Keywords

Anti-inflammatory effect; BV2 cell; Oxoacetamide analogues.

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